Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy

被引：90

作者：

Cheng, Yanli ^{[1
,2
,3
]}

Zhang, Jingjing ^{[3
,4
,5
]}

Guo, Weiying ^{[1
]}

Li, Fengsheng ^{[6
]}

Sun, Weixia ^{[1
]}

Chen, Jing ^{[3
]}

Zhang, Chi ^{[2
,7
]}

Lu, Xuemian ^{[7
]}

Tan, Yi ^{[2
,3
,7
,8
]}

Feng, Wenke ^{[8
,9
]}

Fu, Yaowen ^{[1
]}

Liu, Gilbert C. ^{[10
]}

Xu, Zhonggao ^{[1
]}

Cai, Lu ^{[2
,3
,7
]}

机构：

[1] Jilin Univ, Hosp 1, Changchun 130021, Jilin Province, Peoples R China

[2] Wenzhou Med Univ, Chinese Amer Res Inst Diabet Complicat, Wenzhou 325035, Peoples R China

[3] Univ Louisville, Dept Pediat, Kosair Childrens Hosp Res Inst, Louisville, KY 40202 USA

[4] China Med Univ, Hosp 1, Dept Cardiol, Shenyang 110016, Peoples R China

[5] Peoples Hosp Liaoning Prov, Dept Cardiol, Shenyang 110016, Peoples R China

[6] Second Artillery Gen Hosp, Beijing 100088, Peoples R China

[7] Wenzhou Med Univ, Affiliated Hosp 3, Ruian 325200, Peoples R China

[8] Univ Louisville, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA

[9] Univ Louisville, Dept Med, Louisville, KY 40202 USA

[10] Univ Louisville, Child & Adolescent Hlth Res Design & Support, Louisville, KY 40204 USA

来源：

FREE RADICAL BIOLOGY AND MEDICINE | 2016年 / 93卷

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

Diabetic nephropathy; PPAR alpha agonist; FGF21; Nrf2; Type; 1; diabetes; Oxidative stress; Antioxidants; GROWTH-FACTOR; 21; OXIDATIVE STRESS; BARDOXOLONE METHYL; PPAR-ALPHA; CELL-DEATH; ANTIOXIDANT CAPACITY; KIDNEY-FUNCTION; IN-VIVO; FGF21; ACTIVATION;

D O I：

10.1016/j.freeradbiomed.2016.02.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The lipid lowering medication, fenofibrate (FF), is a peroxisome proliferator-activated receptor-alpha (PPARoc) agonist, possessing beneficial effects for type 2 diabetic nephropathy (DN). We investigated whether FF can prevent the development of type 1 DN, and the underlying mechanisms. Diabetes was induced by a single intraperitoneal injection of streptozotocin in C57BL/6J mice. Mice were treated with oral gavage of FF at 100 mg/kg every other day for 3 and 6 months. Diabetes-induced renal oxidative stress, inflammation, apoptosis, lipid and collagen accumulation, and renal dysfunction were accompanied by significant decrease in PI3K, Alt, and GSK-3 beta phosphorylation as well as an increase in the nuclear accumulation of Fyn [a negative regulator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]. All these adverse effects were significantly attenuated by FF treatment. FF also significantly increased fibroblast growth factor 21 (FGF21) expression and enhanced Nrf2 function in diabetic and non-diabetic kidneys. Moreover, FF-induced amelioration of diabetic renal damage, including the stimulation of PI3K/Akt/GSK-3 beta/Fyn pathway and the enhancement of Nrf2 function were abolished in FGF21-null mice, confirming the critical role of FGF21 in FF-induced renal protection. These results suggest for the first time that FF prevents the development of DN via up-regulating FGF21 and stimulating PI3K/Akt/GSK-3 beta/Fyn-mediated activation of the Nrf2 pathway. (C) 2016 Elsevier Inc. All rights reserved.

引用

页码：94 / 109

页数：16

共 51 条

[1] Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: Results from the Diabetes Atherosclerosis Intervention Study (DAIS) [J].

Ansquer, JC ;

Foucher, C ;

Rattier, S ;

Taskinen, MR ;

Steiner, G .

AMERICAN JOURNAL OF KIDNEY DISEASES, 2005, 45 (03) :485-493

[2]

Badman MK, 2007, CELL METAB, V5, P426, DOI 10.1016/j.cmet.2007.05.002

[3] Role of oxidative stress in diabetic complications - A new perspective on an old paradigm [J].

Baynes, JW ;

Thorpe, SR .

DIABETES, 1999, 48 (01) :1-9

[4] Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis [J].

Brahma, Manoja K. ;

Adam, Rene C. ;

Pollak, Nina M. ;

Jaeger, Doris ;

Zierler, Kathrin A. ;

Poecher, Nadja ;

Schreiber, Renate ;

Romauch, Matthias ;

Moustafa, Tarek ;

Eder, Sandra ;

Ruelicke, Thomas ;

Preiss-Landl, Karina ;

Lass, Achim ;

Zechner, Rudolf ;

Haemmerle, Guenter .

JOURNAL OF LIPID RESEARCH, 2014, 55 (11) :2229-2241

[5] Apoptotic germ-cell death and testicular damage in experimental diabetes: prevention by endothelin antagonism [J].

Cai, L ;

Chen, SL ;

Evans, T ;

Deng, DX ;

Mukherjee, K ;

Chakrabarti, S .

UROLOGICAL RESEARCH, 2000, 28 (05) :342-347

[6] Inhibition of superoxide generation and associated nitrosative damage is involved in metallothionein prevention of diabetic cardiomyopathy [J].

Cai, L ;

Wang, JX ;

Li, Y ;

Sun, XH ;

Wang, LP ;

Zhou, ZX ;

Kang, YJ .

DIABETES, 2005, 54 (06) :1829-1837

[7] Hyperglycemia-induced apoptosis in mouse myocardium -: Mitochondrial cytochrome c-mediated caspase-3 activation pathway [J].

Cai, L ;

Li, W ;

Wang, GW ;

Guo, LP ;

Jiang, YC ;

Kang, YJ .

DIABETES, 2002, 51 (06) :1938-1948

[8] Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy [J].

Cai, Lu ;

Wang, Yuehui ;

Zhou, Guihua ;

Chen, Teresa ;

Song, Ye ;

Li, Xiaokun ;

Kang, Y. James .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2006, 48 (08) :1688-1697

[9] Nrf2 Represses FGF21 During Long-Term High-Fat Diet-Induced Obesity in Mice [J].

Chartoumpekis, Dionysios V. ;

Ziros, Panos G. ;

Psyrogiannis, Agathoklis I. ;

Papavassiliou, Athanasios G. ;

Kyriazopoulou, Venetsana E. ;

Sykiotis, Gerasimos P. ;

Habeos, Ioannis G. .

DIABETES, 2011, 60 (10) :2465-2473

[10] Improvement of inflammatory responses associated with NF-κB pathway in kidneys from diabetic rats [J].

Chen, L. ;

Zhang, J. ;

Zhang, Y. ;

Wang, Y. ;

Wang, B. .

INFLAMMATION RESEARCH, 2008, 57 (05) :199-204

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